Peritoneal adhesions are fibrous tissue connections between abdominal structures following surgical trauma or other types of injury. General abdominal, vascular, gynaecological, urological and orthopaedic surgery may lead to adhesion formation in up to 95% of patients (Ellis et al. 1999. Adhesion-related hospital readmissions after abdominal and pelvic surgery: a retrospective cohort study. Lancet 353, 1476-1480). Post-surgical adhesions are considered the main cause of small bowel obstruction (Menzies et al. 2001. Small bowel obstruction due to postoperative adhesions: treatment patterns and associated costs in 110 hospital admissions. Ann R Coll Surg Engl 83, 40-46.), a well-known aetiology of secondary infertility in females (Marana et al. 1995. Correlation between the American Fertility Society classifications of adnexal adhesions and distal tubal occlusion, salpingoscopy, and reproductive outcome in tubal surgery. Fertil Steril 64, 924-929) as well as a possible cause of postoperative pain (Paajanen et al. 2005. Laparoscopy in chronic abdominal pain: a prospective nonrandomized long-term follow-up study. J Clin Gastroenterol 39, 110-114). More than 30% of individuals undergoing lower abdominal surgery are readmitted for disorders directly or possibly related to adhesion formation at some period of their life (Lower et al. 2000. The impact of adhesions on hospital readmissions over ten years after 8849 open gynaecological operations: an assessment from the Surgical and Clinical Adhesions Research Study. Bjog 107, 855-862.).
In many decades, attempts to reduce post-surgical adhesions by reducing surgical trauma (avoiding desiccation, gentle tissue handling, meticulous hemostasis) and contamination of the abdominal cavity with foreign materials (using starch-free gloves, lint-free gauze and absorbable sutures) have been done (Holmdahl et al. 1997. Adhesions: pathogenesis and prevention-panel discussion and summary. Eur J Surg Suppl, 56-62.). Importantly, the laparoscopic techniques are not sufficient to overcome the problem of post-operative adhesion formation (Duron et al. 2000. Prevalence and mechanisms of small intestinal obstruction following laparoscopic abdominal surgery: a retrospective multicenter study. French Association for Surgical Research. Arch Surg 135, 208-212). Thus, intra-peritoneal adhesions remain a major clinical issue and it is now believed that future improvements may only marginally be influenced through superior surgical technique. Instead, the focus is to develop dedicated products for prevention of adhesion formation, which are administrated in connection to the surgical intervention.
Most of the therapeutic strategies tested in prevention of adhesions are medical device products. Different types of physical barriers have been evaluated, where the biodegradable films applied during the intervention are used to keep the injured abdominal surfaces separated during the critical period of peritoneal healing. The two most widely used adhesion-reducing barriers are Interceed (Johnson & Johnson Medical Inc., Arlington, Tex.) and Seprafilm™ (Genzyme, Cambridge, Mass., USA). Seprafilm™, composed of sodium hyaluronic acid and carboxymethylcellulose (CMC) forms a viscous gel approximately 24-48 h after placement, which is slowly resorbed within 1 week (Diamond, 1996. Reduction of adhesions after uterine myomectomy by Seprafilm membrane (HAL-F): a blinded, prospective, randomized, multicenter clinical study. Seprafilm Adhesion Study Group. Fertil Steril 66, 904-910; Beck, 1997. The role of Seprafilm bioresorbable membrane in adhesion prevention. Eur J Surg Suppl, 49-55). Seprafilm™ has been shown to reduce post-surgical adhesion in clinical situation (Vrijland et al. 2002. Fewer intraperitoneal adhesions with use of hyaluronic acid-carboxymethylcellulose membrane: a randomized clinical trial. Ann Surg 235, 193-199.; Beck et al. 2003. A prospective, randomized, multicenter, controlled study of the safety of Seprafilm adhesion barrier in abdominopelvic surgery of the intestine. Dis Colon Rectum 46, 1310-1319; Tang et al. 2003. Bioresorbable adhesion barrier facilitates early closure of the defunctioning ileostomy after rectal excision: a prospective, randomized trial. Dis Colon Rectum 46, 1200-1207), however, the device is difficult to apply, as it adheres to gloves and organs and is brittle (DeCherney & diZerega, 1997. Clinical problem of intraperitoneal postsurgical adhesion formation following general surgery and the use of adhesion prevention barriers. Surg Clin North Am 77, 671-688). Additionally, Seprafilm™ increases the risk of sequelae associated with anastomosic leak and is not compatible with laparoscopic procedures (diZerega et al. 2002. A randomized, controlled pilot study of the safety and efficacy of 4% icodextrin solution in the reduction of adhesions following laparoscopic gynaecological surgery. Hum Reprod 17, 1031-1038). Interceed, composed of oxidized regenerated cellulose, is transformed into a gelatinous mass covering the injured peritoneum and has shown efficacy in adhesion-prevention in several clinical studies (Mais et al. 1995. Prevention of de-novo adhesion formation after laparoscopic myomectomy: a randomized trial to evaluate the effectiveness of an oxidized regenerated cellulose absorbable barrier Hum Reprod. 10, 3133-3135; Mais et al. 1995 Reduction of adhesion reformation after laparoscopic endometriosis surgery: a randomized trial with an oxidized regenerated cellulose absorbable barrier Obstet Gynecol. 86, 512-515; Wallwiener et al. 1998. Adhesion formation of the parietal and visceral peritoneum: an explanation for the controversy on the use of autologous and alloplastic barriers? Fertil Steril 69, 132-137). However, application of Interceed requires complete hemostasis as even small amounts of intraperitoneal bleeding negates any beneficial effect of this barrier (DeCherney & diZerega, 1997. supra). A general limitation of using the physical barriers is the site-specificity of the product, requiring the surgeon to predict where adhesions will occur and where they would most likely cause clinical problems. As an alternative to barriers, different fluids for intra-abdominal instillation such as icodextrin (Adept, Baxter Healthcare Corporation, IL, USA) or lactated Ringers' solution, have been administrated after the surgery in volumes sufficient to allow floatation of the abdominal structures and thus preventing the injured surfaces from reaching each other (Yaacobi et al. 1991. Effect of Ringer's lactate irrigation on the formation of postoperative abdominal adhesions. J Invest Surg 4, 31-36; Cavallari et al. 2000. Inability of University of Wisconsin solution to reduce postoperative peritoneal adhesions in rats. Eur J Surg 166, 650-653.; diZerega et al. supra). However, the gravity causes problems by preventing even distribution of the fluid in the abdomen. Also, the solutions are absorbed more rapidly from the abdominal cavity than the time required for peritoneal healing.
A limited number of pharmacologically active compounds have been tested in prevention of post-surgical adhesions. As some examples, the inflammatory component and fibroblast proliferation of the wound healing cascade has been a target of pharmacotherapy by using steroids drugs and cytotoxic drugs, respectively. However, these agents have shown ambiguous efficacy and potentially serious side effects (LeGrand et al. 1995. Comparative efficacy of nonsteroidal anti-inflammatory drugs and anti-thromboxane agents in a rabbit adhesion-prevention model. J Invest Surg 8, 187-194; Li et al. 2004. Synthesis and biological evaluation of a cross-linked hyaluronan-mitomycin C hydrogel. Biomacromolecules 5, 895-902).
Due to the limited efficacy and difficult handling of the tested therapies, the vast majority of surgical interventions performed in abdominal cavity today, do not apply any products to prevent adhesion formation and the post-operational adhesions continue to cause suffering for the patients and present the major cost for society (Ray et al. 1998. Abdominal adhesiolysis: inpatient care and expenditures in the United States in 1994. J Am Coll Surg 186, 1-9.; 2005).
The object of the present invention is to provide a means which has the ability to prevent the formation of post-operative adhesion formation without having the unwanted side effects of the currently available pharmaceutical compositions, devices and procedures.